New-And-Emerging-Technologies-For

Horizon Scanning Centre)

New and emerging self-sampling technologies for Human Papillomavirus (HPV) testing

March 2014

This report presents independent research funded by the National Institute for Health Research (NIHR). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

The NIHR Horizon Scanning Centre, University of Birmingham, United Kingdom [email protected] http://www.hsc.nihr.ac.uk/

CONTENTS

CONTENTS Executive summary ………………………………………………………………………… 5 Acknowledgments ...... 5 1. Introduction ...... 6 1.1 NHS Cervical Screening ...... 6 1.2 HPV testing ...... 7 1.3 HPV self-sampling …………………………………...…………………………………... 7 1.3.1 Proof of concept ...... 8 1.3.2 Technology types ...... 9 1.4 Aim & objective …………………………………………………………………………. 10 2. Methods ...... 10 2.1 Inclusion criteria ...... 10 2.2 Review process ...... 11 2.2.1 Identification of technologies ...... 11 2.2.2 Expert advice ...... 12 3. Results ...... 12 3.1 Technologies by type...... 13 3.2 Sample transit – dry versus liquid…...... 13 4. Discussion ...... 14 4.1 The sampling device – what matters? …...... 14 4.1.1 User acceptability ...... 15 4.1.2 Sampler design ...... ……….15 4.1.2.1 Applicator or stick?...... 15 4.1.2.2 Swab or brush?...... 16 4.2 Sampling method …………………………………………………………………..…... 17 4.2.1 Instructions for use...... 17 4.2.2 Accidental detachment ...... 17 4.3 Post-sampling method …………………………………………………………………..17 4.3.1 Sample transfer...... 17 4.3.2 Dry or liquid? ...... 17 4.3.3 Labelling and consent ...... 18 4.4 Transportation …………………………………………………………………………... 18 4.4.1 Dry transportation...... 18 4.7 Cost……………………...... 19 4.8 Innovations in HPV testing……...... 19 5. Summary ...... 19

3 Appendices Appendix 1 Advisory Group ………………………………………………………………... 20 Appendix 2 Technologies marketed or in development for HPV self-sampling use .... 21 Appendix 3 Technologies that might have potential for HPV self-sampling use …...... 28 Appendix 4 Pictures of some of the technologies ……………………………..……….... 38 References ……………………………………………………………………...…………... 45

EXECUTIVE SUMMARY

This review aims to identify new and emerging technologies for cervicovaginal self- sampling for human papillomavirus (HPV) testing. Infection with HPV is the main risk factor and a necessary cause of cervical cancer. Cervical cancer is the twelfth most common cancer in women in the UK, and the third most common gynaecological cancer1. It caused 781 deaths in England in 20112. The NHS Cervical Screening Programme screens over three million women in England each year3.

In order to identify relevant technologies, the review used five sources of intelligence:

1. Consultation with:

• commercial developers. • clinical and scientific experts. • trade associations.

2. Searching:

• online sources of information (e.g. clinical trial and bibliographic databases, and the medical media). • NIHR Horizon Scanning Centre in-house technology database.

A total of 43 technologies were identified. Of these, 17 are either currently marketed (or are being developed) specifically for self-sampling use. The remaining 26 technologies might have potential for self-sampling use.

ACKNOWLEDGEMENTS

Internal review team Dr Sara Trevitt Senior Analyst Dr Sue Simpson Associate Director Dr Annette Wood Medical Advisor

Advisory Group Ms Catherine Witney NHS Cancer Screening Programmes Mrs Janet Rimmer NHS Cancer Screening Programmes Ms Samantha Fletcher Central Manchester University Hospitals NHS Foundation Trust Dr Kate Cuschieri Scottish HPV Reference Laboratory.

1. INTRODUCTION

The review was conducted at the request of the NHS Cancer Screening Programmes (a part of Public Health England) to provide an early intelligence report on new and emerging self-sampling technologies that can or could potentially be used for HPV testing.

1.1 NHS CERVICAL SCREENING

Cervical screening is a method of preventing cancer by detecting and treating early abnormalities which, if left untreated, could lead to cancer in a woman's cervix (the neck of the womb)4. In England, the NHS Cervical Screening Programme (NHSCSP) offers cervical screening to all women aged between 25 and 64 years. After the first cervical screen, repeat invitations are sent out every three years between the ages of 25 and 49 years and every five years between the ages of 54 and 64 years.

Current cervical testing uses a method called liquid-based cytology (LBC). The sample is taken by a healthcare professional (nurse or doctor) in a primary care setting, such as a GP surgery. An instrument called a speculum is inserted into the vagina to hold it open, whilst a small brush-like device is wiped over the cervix to pick up cells. This sample of cells is then placed into a small container of liquid. Obtaining the sample takes a few minutes, and some woman may experience some discomfort or pain. The sample is then sent to a laboratory for the cells to be transferred onto a slide and examined microscopically (called cytology).

More than 3.5 million women were screened by the NHS Cervical Screening Programme in England in 2011/20125. According to figures reported in 2012, cervical screening coverage in England (the proportion of women screened within the previous five years) has remained consistently high over the past 20 years5. However, there has been a gradual decline from 82% coverage in the late 1990s to 79% in the five years up to 2012. The fall in coverage of 0.3% (78.6% down to 78.3%) between March 2012 and March 2013 was most notable among women aged 25 to 49 years6.

The reasons that women do not attend for screening are complex, but include7:

• Emotional/personal barriers, e.g. embarrassment, fear of discomfort or pain, fear of the result, preference for a female nurse/doctor. • Practical and organisational barriers, e.g. travel difficulties, childcare issues, work commitments. • Knowledge/awareness barriers, e.g. lack of understanding about the causes of cervical cancer and the purpose of screening. • Demographic factors, e.g. being from a specific ethnic minority group or a deprived background.

Cervical cancer caused 781 deaths in England in 20112. Many women who develop the disease have not been screened regularly, and not undergoing cervical screening is one of the greatest risk factors for developing cervical cancer. Regular cervical screening is the best way to detect changes to the cervix before cancer develops. Early detection and treatment can prevent around 75% of cervical cancers from developing4.

6 Cervical cancer is more common in women who smoke, first had sex at an early age, have had several sexual partners, have had a sexual partner who has had several other partners, or take immunosuppressant drugs.

1.2 HPV TESTING

Human papillomavirus (HPV) is a common infection that most women will get at some time in their life. It shows no symptoms. HPV is easily transmitted during intimate sexual contact between partners. There are many types of HPV, some of which are ‘high risk’ types (hrHPV) for causing abnormalities in the cervix. If the infection is left untreated, in some cases these abnormalities may develop into cervical cancer. However, not all abnormalities develop into cancer, and in many cases HPV infection clears up by itself.

HPV testing can be used at three points in the screening pathway:

1. Primary screening8 – as the first test performed and done on all samples. Often referred to as ‘HPV first’.

2. HPV triage9 – as the second test and done only on samples that have abnormal LBC results.

3. HPV test of cure9 – following treatment, to check whether or not it has worked.

HPV triage and HPV test of cure were both introduced into routine cervical screening in England in 2012. The use of HPV testing for primary screening (HPV first) is currently being evaluated in a pilot research study at six centres in England8. The clinical performance of HPV testing technologies depends on which of these three clinical contexts they are used in and also on the characteristics of the population being tested. High risk HPV tests that have been clinically validated for use in HPV first include: Hybrid Capture 2 (HC2, from Qiagen), GP5+/6+ PCR (no specific developer), cobas 4800 (from Roche), RealTime High Risk HPV PCR assay (from Abbott Molecular) and also Papillocheck (from Bio-Greiner)10.

1.3 HPV SELF-SAMPLING

There is currently much interest in the possibility of offering home-based self-sampling for HPV testing for the primary screening of women who are not currently accessing cervical screening. This so-called group of ‘non-responders’ accounts for around two in ten women in England5. It is hoped that offering this new testing option might overcome some of the barriers that can prevent women from getting screened, and thereby potentially reduce the number of deaths from cervical cancer.

High risk HPV testing can be performed on self-collected cervicovaginal samples because the virus spreads from the cervix down into the vagina and intact cervical cells are not needed to demonstrate the presence of the virus (unlike with LBC)11. The Netherlands is the first country to offer self-sampling for HPV testing to non- responders12, with Mexico also following suit13,14. In the UK, a research study called STRATEGICa,15 is comparing the use of two self-sampling technologies along with a Full study title: STRATEGIes to increase Cervical screening uptake at first invitation: a cluster randomised trial

7 other interventions aimed at increasing screening uptake and is due to complete in October 201516.

1.3.1 PROOF OF CONCEPT

A large body of evidence indicates that self-sampling for HPV testing is a viable option both in terms of clinical validity and acceptability to women17,18,19,20,21,22. Most research studies to date (over 94% according to a recent review17) have compared the results obtained from self-collected samples with those collected by a healthcare professional (‘clinician-collected’). However, a variety of different types of self-sampling devices and transportation methods exist and little research has compared these against each other. Other factors relevant to strategic planning for HPV testing include rapid innovation in tests, platform automation and biomarkers for HPV, and changes in the population who are affected by HPV that may result from the national HPV immunisation programme in England (which began for girls aged 12-13 in 200823).

A recent meta-analysis by Arbyn et al (2014)17 summarised data from 36 research studies that compared HPV DNA screening using self-collected and clinician-collected samples with cytology in terms of their clinical accuracy to detect CINb grade 2 infection or worse (known as CIN2+) and CIN grade 3+ infection in a variety of clinical settings. The 36 studies were identified for the period March 1990 to June 2013, which altogether involved 154,556 women. The authors concluded that HPV testing on self- samples using assays based on a molecular technique called signal-amplification was less sensitive and specific than testing on clinician-collected samples. In contrast, some assays based on a technique called PCRc showed generally similar sensitivity on both self-samples and clinician-collected samples. Of the 36 studies identified, 16 (from 14 papers) were looking at primary screening of healthy women. In the context of screening, the authors found that HPV testing on self-collected samples detected on average 76% (95% CId 69–82%) of CIN2+, and 84% (95%CI: 72–92%) of CIN3+. The pooled absolute specificity to exclude CIN2+ was 86% (95% CI: 83–89%) and 87% (95% CI: 84–90%) to exclude CIN3+. According to a published commentary on this meta-analysis, the self-collection of samples resulted in an 11% reduction in test sensitivity compared to clinician-collection18.

Impact on participation in screening A recent systematic review19 of methods to increase participation in organised screening programmes searched for papers published between January 1999 and July 2012. Seven studies (all published 2010-2012) were identified that compared the use of a self-sampling device for HPV testing with recall for screening at a clinic in non- responders. These studies represented 18,022 self-sampling events (153 of which were in the UK24). The authors concluded that posting a home-use self-sampling device to non-responders significantly increased participation in cervical cancer screening.

b CIN: Cervical Intraepithelial Neoplasia (the precursor of cervical cancer) c PCR: polymerase chain reaction d Confidence interval

1.3.2 TECHNOLOGY TYPES

Sampling Devices for sample collection come in four basic types: 1. Brush 2. Swab 3. Lavage 4. Tampon.

Designs vary from the simple ‘stick-style’ cytobrushe or cervical swab (a stick with a specially designed sampling brush or swab head on one end), to more complicated devices comprised of a plunger-based ‘applicator’ (insertion device) with a brush, swab or lavagef liquid inside.

Transportation Sample transportation may take four forms:

1. The collection device (or just the head section of it) is placed into an empty container (e.g. tube/vial or bottle). 2. The collection device (or just its head section) is placed into a container containing liquid Specimen Transport Medium (STM)/HPV testing medium. 3. The head section of the collection device is rubbed gently onto a solid transportation device (e.g. FTAg card) to transfer the sample. 4. The lavage liquid is emptied into an empty container.

The sample is transported in a ‘dry’ state in methods 1 and 3, and a ‘liquid’ state in methods 2 and 4. Some transportation containers are generic in type, while others are specially designed to fit directly with laboratory equipment (to reduce handling and improve workflow).

Table 1 shows the number of studies identified in a recent meta-analysis17 using the four types of collection device for the three main tests that have been clinically validated for primary screening, using clinician-collected samples.

Table 1: Number of published studies on the use of self-collection device types with validated HPV first assays (adapted from a meta-analysis by Arbyn et al 201417).

HPV test Studies by type of collection device Brush Swab Lavage Tampon Hybrid Capture 2 (HC2) 8 7 2 1 GP5+/6+ PCR 3 0 2 0 Abbott Real Time hrHPV Test 0 0 1 0 Total studies identified 11 7 5 1

e Cytobrush: small brush that is used to sample cells from the vagina, cervix or endocervix f Lavage: irrigation or washing out of an organ or cavity g FTA: Flinders Technology Associates

This meta-analysis also reported relative sensitivity and specificity by types of self- collection device (Table 2).

Table 2: Number of published studies, relative sensitivity and relative specificity by self- collection device: self-collected versus clinician-collected (adapted from a meta-analysis by Arbyn et al 201417).

Self- Number of studies (number Relative sensitivity Relative specificity collection of test/device combinations) device type Brush 18 (24) 0.89 (9.83-0.93) 0.98 (0.97-0.99) Lavage 5 (6) 0.94 (0.85-1.03) 0.95 (0.68-1.34) Swab 10 0.86 (0.80-0.92) 0.95 (0.90-1.01) Tampon 1 0.71 (0.62-0.83) 1.01 (1.00-1.02)

It should be noted that these results were derived from data pooled from a range of different study protocols and clinical scenarios. In order to evaluate candidate technologies for self-collection and transportation of samples, clinical validation would be needed in the context of the relevant population and intended ‘HPV-first’ testing protocol. Other key issues would include ease of integration into the current cervical screening programme, the cost and logistics of service delivery, and how to launch and promote public awareness of a new home-based option for screening.

1.4 AIM & OBJECTIVE

The aim of this review was to identify new and emerging technologies for self-sampling for HPV testing. The objective was to research this topic and provide a report to the NHS Cancer Screening Programmes. The information in the report will also be of interest to other stakeholders such as the Department of Health, commissioners, clinicians and patient groups, as well as organisations such as Cancer Research UK, the Technology Strategy Board and other NIHR programmes including the Heath Technology Assessment (HTA) and Efficacy and Mechanism Evaluation (EME) Programmes.

The report has been informed by advice from experts. It does not provide a comprehensive overview of all new and emerging technologies for self-sampling for HPV testing, but instead reports on those most likely to have a potential for impact on the NHS Cervical Screening Programme and healthcare resources.

2. METHODS

2.1 INCLUSION CRITERIA

The inclusion criteria were:

Technology type Technologies for self-collection and/or transportation of samples for laboratory HPV testing:

10 • Complete kits (commercially packaged product combinations or ‘ad hoc’ kits). • Sample collection devices. • Transportation technologies.

Timeframe h • New – CE marked already or expected to be so within the next 12-24 months, or • Emerging – expected to be launched in the UK within the next 12-24 months.

2.2 REVIEW PROCESS

The review strategy comprised the following elements:

• Searching online and in-house sources of intelligence and contacting research groups and commercial developers to identify potentially relevant technologies. • Researching the technologies to establish relevance and provide detail. • Consulting with researchers in the field and an Advisory Group to add value to the intelligence reported on. The Advisory Group (Appendix 1) was established at the outset of the project.

2.2.1 IDENTIFICATION OF TECHNOLOGIES

The first step was to identify technologies that met the inclusion criteria. The review process involved researching the following kinds of sources of intelligence:

• General internet searching using Google for medical media reports, review articles, etc. • Research publications, e.g. via Medline and conference abstracts. • Members-only access of international horizon scanning databases, e.g. EuroScan (www.euroscan.org.uk). • Clinical trial registries. • Industry intelligence, including developers’ websites, consultation with trade associations and industry press releases. • The Horizon Scanning Centre’s in-house technology database.

During the identification stage, it became apparent that many technologies are being used in research into HPV self-sampling use, despite the fact that they are not currently marketed for this indication. Another feature of the review was that the products used in research were often vaguely described (e.g. the ‘usual brush from Qiagen’) or were referred to using several different names or pseudonyms (e.g. the ‘Christmas tree’ sampler). This meant that extensive correspondence with researchers was needed to establish which technology had been used in a study and what its official name was, thereby eliminating duplicate technologies.

The websites of developers (mainly commercial companies) in the field were investigated as part of the search strategy to identify technologies. Developers were contacted by email or telephone to obtain information on potentially relevant technologies. Non-responding developers were contacted between two and four times

h CE marking means that a product is approved for sale in the EU (i.e. it conforms with EU product directives)

11 to try and elicit a response. Companies that appeared to have potentially relevant products were invited to complete a technology information questionnaire about them. All requests for further information or clarification were chased up to four times.

2.2.2 EXPERT ADVICE

The search process produced an initial long-list of technologies, which were then further researched to confirm their relevance, eliminate duplicates, and provide further detail. Following this in-house filtration process, the long-list of technologies was then sent to the Advisory Group to comment on aspects such as innovation, user- acceptability, potential benefits and barriers to adoption, timeframe for impact within the NHS, and the state of the evidence base and need for further research. The purpose of consulting with experts was to add value to the intelligence that the Horizon Scanning Centre provided to the NHS Cancer Screening Programmes, and their comments are incorporated into the discussion section.

3. RESULTS

The websites of 63 developers were investigated to identify relevant technologies. Following this, 38 developers were contacted for information on products, including their intended indications, novel features, stage of development and UK availability. Of the 38 contacted, 27 responded (71%), although the completeness of their responses varied. Eleven developers did not respond, despite being contacted up to four times. Fifteen developers (those that appeared from their websites to have relevant products) were invited to complete a ‘technology information questionnaire’ about each of their technologies, 12 (80%) responded. Of the 43 researchers contacted for information and advice, 22 responded (51%). This was in addition to the Advisory Group members.

The research process identified 78 potentially relevant technologies. Upon further investigation, 35 of these were eliminated as they either did not meet the review criteria or were duplicates. This in-house filtration produced a final list of 43 technologies which was divided into two sets according to likely relevance:

A. Technologies that are either marketed or in research development for self- sampling use: a total of 15 technologies were identified. Information on 13 of these 15 technologies is publically available, and is presented in this report (Appendix 2).

B. Technologies that might have potential for self-sampling use in the future: a total of 28 were identified (Appendix 3). Many of these have been, or are being, used for self-sampling use in research.

Pictures of seven of the technologies in group A are provided in Appendix 4.

3.1 TECHNOLOGIES BY TYPE

A summary of the number of technologies identified by type is shown below (Table 3). Of the 43 technologies identified, 19 were kits, 15 were collection devices and 9 were transportation technologies. The most common type of sampler was brush-based (18 technologies), followed by swab-based (12 technologies). Of the 34 kits and collection devices identified, nine (26.5%) used an applicator device for insertion into the vagina. The remaining 25 technologies (73.5%) were based on a more simple ‘stick’ type design.

Table 3: Identified technologies categorised by type.

Marketed or in Might have Total Technology type development for potential for technologies self-sampling use self-sampling (n) (n) use (n) Swabs 12 Swab 0 3 3 Swab + tube - KIT 3 4 7 Swab/applicator only 1 0 1 Swab/applicator + tube - KIT 1 0 1 (can also be an all-in-one kit) Brushes 18 Brush 2 7 9 Brush + tube - KIT 0 5 5 Brush/applicator all-in-one KIT 3 0 3 Brush + FTA card - KIT 1 0 1 Other collection devices 4 Lavage/applicator + tube - kit 1 0 1 Tampon 1 1 2 ‘Sampling tool’/applicator 1 0 1 Transportation technologies 9 Liquid transport technology (STM) 0 4 4 Solid transportation technology 1 1 2 (FTA device) Transportation device (vial) 0 3 3 Total number of technologies 15 28 43

3.2 SAMPLE TRANSIT – DRY VERSUS LIQUID

Of the 34 kits and collection devices identified, 22 used (or could use) a liquid form of sample transit, and 13 used (or could use) a dry form of transit (Table 4). These figures

13 are based on the interpretation of product information, and where this was not available on the mode of transit used in the research studies identified. Other modes of transit may be possible or may have been used in research studies which were not found, and therefore these figures should be interpreted as estimates.

Table 4: Identified kits and collection devices categorised by mode of transport.

Technology type Liquid transit Dry transit Both liquid or dry Not known Kit 9 6 3 0 Collection device 6 1 3 6 Total (n=34) 15 7 6 6

4. DISCUSSION

In our search of the literature, we did not find much published research that compared self-sampling technologies and methods with each other (or their use in different combinations). In order to compare different candidate self-sampling technologies, clinical performance would need to be evaluated in the context of the full testing protocol used, i.e. for each specific combination of self-collection/transportation (technologies and methods) plus HPV testing system25. Relevant parameters for comparison would include clinical performance, acceptability to women, compatibility with the current screening programme, costs and logistics.

The methods both for sampling and preparation of the sample for transportation would need to be as safe, simple and streamlined as possible whilst keeping costs low. Many researchers have mix-and-matched elements of different kits/products and methods to form ad hoc (in-house) kits. It was for this reason that elements of kits (e.g. the brush component) were presented both separately and as part of the complete kit in our technology tables. The following discussion presents the main issues highlighted by the Advisory Group, the international experts consulted, and in recent published reviews of the field.

4.1 THE SAMPLING DEVICE – WHAT MATTERS?

A systematic review26 of research papers on vaginal self-sampling for HPV DNA testing referenced in PubMed from 1990 to March 2013, found that self-collection was generally well-accepted and may be preferred to speculum-based cervical sampling. Most measures of acceptability, including pain, embarrassment and anxiety favoured the self-collection approach. However, 50-70% of women worried that they would not take the sample properly. In personal communication, an expert commenting on the review said that she had not found any obvious effects in terms of which sampling device was used, although the studies that compared devices were usually inadequately done and very small. This review suggests that the device used is not particularly important, as long as it is acceptable to women and meets cost goals. Newer devices that are being developed may change these conclusions but they have not been studied fully. Another expert agreed with this view, maintaining that the only important characteristics of the collection device are (a) how acceptable it is to women

14 and (b) how cheap it is. He added that the effectiveness of self-sampling depends on the HPV assay used.

An expert commented that, based on focus group testing and the international literature about acceptability, a simple ‘non-threatening’ device is essential to improve participation. They also stated that the device should be cheap. They added that recent data for studies that have used PCR-based HPV tests show that the type of HPV test used is more important than the sampling device itself. In other words, if a PCR-based test is used, sensitivity for self-collection is similar to that obtained from a clinician- collected specimen, and both are significantly more sensitive than cytology. A French expert said that she had had good experience with both the digene Cervical Sampler brush (Qiagen) and Dacroni swab, which were well accepted by women. Her view is that the device does not affect the quality of the samples and DNA HPV tests can be run from samples collected with either of these devices. She thinks that the main issue is acceptability to women, which is related to social and cultural aspects.

For a self-sampling (and transportation) technology to be considered for use in the NHS Cervical Screening Programme, it would need to have potential for use with the HPV tests currently employed within the programme. It might also be useful if the self- collected sample could be used for triage with either cytology and/or biomarker analysis. However, it was not within the remit of this review to consider how self- sampling might be integrated into the current (or future) cervical screening programme.

4.1.1 USER ACCEPTABILITY

Factors that are likely to affect how acceptable the sampling device/s and method are to women may include the following:

• Does the kit look safe, easy and comfortable to use? • Is this perception matched by actual user experience? • Are the instructions for use clear, quick and easy to follow? • Are there worries about potential issues like the sampler breaking during use, not being able to do the sampling/preparation for transportation correctly, or spilling liquids?

4.1.2 SAMPLER DESIGN

4.1.2.1 APPLICATOR OR STICK?

Almost three-quarters (73.5%; 25 technologies) of the sampling technologies identified were based on a simple stick design (stick with a swab or brush head). Just over a quarter (26.5%, 9 technologies) had a more bespoke applicator-style design, e.g. technologies 1-3 in Appendix 2 ( Figures 1-3, Appendix 4).

One expert thought that devices that look similar to related everyday personal items (e.g. a tampon with applicator, such as technologies 1-3 in Appendix 2) may appeal to women. This type of device will be familiar to many women and is likely to be i Dacron: the brand name of a synthetic polyester fabric (also known as Terylene)

15 associated with reasonably comfortable use and safety. Another type of fairly familiar home-use device is a Canestan® pessary with applicator (for the treatment of vaginal thrushj), although not as many women may be familiar with using these. In terms of other self-sampling devices, vaginal swabs are used for sexually transmitted infection (STI) sampling in Genito-Urinary Medicine (GUM) clinics, and some women may have had experience of using these in a clinic setting. Another expert suggested that a more elaborate, bespoke-design (e.g. ergonomic shape, shiny pink/pastel-coloured plastic casing, e.g. technologies 1-3 in Appendix 2; Figures 1-3 in Appendix 4) might appeal to some women as it may appear to be more purpose-made and ‘professional’.

A UK researcher has said that their team has done some acceptability work and found that when women are shown a range of devices (including the bespoke-style Rovers Evalyn Brush and Delphi Screener, technologies 1 and 2 in Appendix 2) they tend to choose a Dacron swab (e.g. technologies 23, 28 and 30 in Appendix 3). A simple stick format (e.g. technologies 7, 11 and 12 in Appendix 2 and 23-32 in Appendix 3), with less plastic and less packaging may be more appealing to some women. It might also be a less costly product, cheaper to transport, and with a lower environmental impact. Further research is needed to establish user preferences in the relevant population.

4.1.2.2 SWAB OR BRUSH?

A sampler head that has a soft appearance such as a fabric swab made of cotton or Dacron (e.g. technologies 4 and 7 in Appendix 2, and 14, 16-17, 22-23, 28 and 30 in Appendix 3) may look like it would be more comfortable to use than a brush head (e.g. technologies 11-12 in Appendix 2, and technologies 24-27, 29 and 31-32 in Appendix 3). Women are also more familiar with the properties of a regular cotton bud, and may therefore perceive a swab as being soft and yet robust. An American researcher said they used a cotton swab in preference to a brush in their studies, as this had been found to be more acceptable to their participants. Another issue might be that some women may be tempted to touch a brush head, just to check how soft or scratchy it feels, leading to contamination from the fingers.

In terms of sample collection, it has been suggested that brushes (e.g. technologies 11- 12 in Appendix 2, and technologies 24-27, 29 and 31-32 in Appendix 3) obtain samples closer to the cervix and achieve a higher sample yield than swabs. Proponents of brush-based sampling also say that although swabs absorb the sample easily, it is more difficult to get the sample out of the swab for testing in the laboratory. Evidence for and against these points was not sought in this review, but comparisons based on home-based self-sampling would be needed. An American researcher said that their team stopped using swabs some time ago because the swabs collected fewer cells and were not cheaper than brushes, although he added that they had not tested swabs with PCR-based assays. A French researcher who has studied the use of both brush and swab thinks that the sampling device used does not affect the quality of the sample, and that both work well. However, a Dutch report has suggested that the testing results obtained using a brush (e.g. technologies 11-12 in Appendix 2, and technologies 24-27, 29 and 31-32 in Appendix 3) or lavage sampler (e.g. technology 2 in Appendix 2) show greater sensitivity for detecting CIN2+ than those collected using a swab (e.g. technologies 4 and 7 in Appendix 2, and 14, 16-17, 22-23, 28 and 30 in Appendix 3)11.

4.2 SAMPLING METHOD

4.2.1 INSTRUCTIONS FOR USE

One expert suggested that in addition to written instructions for use (with different language versions), there should also be clear step-by-step diagrams and a video web- link illustrating the complete sampling process aimed at the user. One of the technologies identified had an online instruction video which ran for almost eight minutes, which the expert thought was too long.

4.2.2 ACCIDENTAL DETACHMENT

The experts thought that some women may have concerns that the head portion of the sampling device might become detached from the stick during use, potentially leaving it inside the vagina and needing to be retrieved. This concern may potentially apply to several of the samplers, including technologies 6-7 (Appendix 2), 16-17 and 23 (Appendix 3).

4.3 POST-SAMPLING METHOD

4.3.1 SAMPLE TRANSFER

Several of the devices identified require the sampler head to be detached (usually by snapping it) from the main stick for transfer into a tube or bag for transportation. Examples include technologies 6-7 and 11 (Appendix 2) and 16-17 (Appendix 3). The consensus of the experts consulted was that this step might not appeal to users and may also increase the risk of accidental liquid spillage or sample contamination (e.g. from touching or dropping the sampler head).

4.3.2 DRY OR LIQUID?

Several experts had safety concerns about the potential hazards of using a preservative liquid transport medium, both in the home and during transit. Examples of technologies in which the sample is transported in such liquid-based systems include technologies 7 (Appendix 2), and 14-21, 26, 27, 29 and 32 (Appendix 3). One expert suggested that the use of saline (salt solution) might be a safer alternative (this is the liquid used in technology 2, Appendix 2). According to an American expert, liquids are generally cheap, compatible with most assay systems and easier to automate. However, they spill, are more complicated to handle, and are more expensive to transport due to weight.

As for dry methods of transportation, one expert expressed concerns that transferring the sample to a card or cartridge (e.g. technology 34, Appendix 3) for transportation might increase the risk of contamination with DNA not derived from the vagina or cervix (e.g. from the fingers if they touch the card/cartridge). An American expert said that solid media transport cards are a bit more expensive at present, but they render the DNA stable, the sample non-infectious and require elution of the DNA in the laboratory

17 rather than a DNA extraction step. He said that they are easy for untrained people to handle, weigh almost nothing and take up minimal space for posting.

According to an expert, the choice between dry versus liquid transit (STMk or PreservCyt), depends on the test that will be used. She said that most tests are validated on liquid-based samples and believes that most (including HC2) are not validated on dry samples. She also thinks that dry samples need to be frozen quickly to preserve them until testing, while liquid-based samples can be at room temperature for several days or even a few weeks before testing without any problem. In her view the only advantage of dry samples is that is that you save money and do not have to worry about risks such as children at home drinking the medium. Otherwise, she thinks that liquid-based transport is better.

4.3.3 LABELLING AND CONSENT

One expert had concerns about the need for a woman to correctly fill in and attach a hand-written sticker with identifying details and also to complete a handwritten consent form. She thought it better if unique identification details (ID number/barcode/smart code), with corresponding consent forms could be pre-printed and attached to the correct component before the kit is sent out. This would reduce the risk of problems with sample identification and lack of consent.

4.4 TRANSPORTATION

4.4.1 DRY TRANSPORTATION

Options for dry transportation include immediately placing the sampler into a container and envelope before posting (e.g. technologies 4, 5 and 11 in Appendix 2, and 22-23 in Appendix 3), or allowing it to air dry before doing so (technology 6 in Appendix 2). Another option is to transfer the sample to a specially designed card or cartridge for transportation (e.g. technologies 5 and 12, Appendix 2). The latter has the claimed advantage of confirming with a colour change when the sample has been successfully transferred. This may increase compliance and perceived ease of use.

According to a recent literature review20 about self-sampling as a cervical cancer screening strategy, the development of dry (rather than liquid-based) specimens should be a research priority. Dry transportation technologies would need to be able to stabilize DNA, render specimens non-infectious, withstand variations in temperature and humidity, and be resistant to cross-contamination. The review authors believe that the iFTAe micro card (technology 34, Appendix 3) may be one such technology. They suggest that alternative inexpensive solutions might include fixation with common materials such as hairspray, or simply air-drying on the collection device. Some dry methods of transit may be cheaper to transport.

According to a UK expert, the iFTAe card (technology 34 in Appendix 3) can be used with a self-sampling brush. The sample is stable in the card and can be posted to the laboratory for analysis. The discs from the sample are punched from the card and DNA is eluted with a water step ahead of PCR. k STM: Specimen Transport Medium

4.7 COST

Sampling devices with more elaborate bespoke designs (e.g. technologies 1-3 in Appendix 2) tend to be more expensive than the basic stick format. The use of greater quantities of packaging materials and liquid transportation may increase transportation costs (and environmental impact). The use of pre-printed and attached user-unique identification information (e.g. barcodes), and of advanced sample tracking technologies are also likely to increase costs.

4.8 INNOVATIONS IN HPV TESTING

HPV testing is currently an area of rapid innovation, with the development of new HPV assays with different performance characteristics, and automated platforms capable of high volume testing. There are also a number of emerging HPV biomarkers in late phase development. According to a recent review27, testing for nucleic acids of hrHPVs or for cellular surrogate markers of HPV transforming processes is an area of great potential for cervical screening. Emerging biomarkers include14,27.

• p16ink4a/K1-67 overexpression • E6-E7 mRNA overexpression • E6 protein overexpression • minichromosome maintenance protein 2 (MCM 2) • Topoisomerase II alpha (TOP2A) proteins. • MYBL2 • Survivin • Methylation - particularly of CADM1 (host) and L1 and L2 genes (virus).

5. SUMMARY

A considerable body of evidence suggests that HPV self-sampling could be a viable option for primary cervical screening in non-responders. However, relatively little research has so far focused on comparing the technical performance and user- acceptability of different self-sampling technologies and methods. Practical issues remain around the use of self-sampling for HPV testing, as commented on by both UK- based and international experts. These issues include the design of the sampling device, the method by which the sample is prepared for transportation to the laboratory, the mode of transportation (options for both dry and liquid transit), cost, and labelling and consent.

Forty-three technologies were identified, of which 17 are currently available or are in development for self-sampling use. The remaining 26 technologies may also be of relevance, and many of them are already being used in research into self-sampling for HPV testing.

APPENDIX 1 – ADVISORY GROUP

• Ms Catherine Witney - Laboratories Coordinator NHS Cancer Screening Programmes, Public Health England. • Mrs Janet Rimmer - Coordinator (Laboratories), NHS Cancer Screening Programmes, Public Health England. • Ms Samantha Fletcher - Research Midwife, Central Manchester University Hospitals NHS Foundation Trust. • Dr Kate Cuschieri (technical advisor) - Director, Scottish HPV Reference Laboratory, Royal Infirmary of Edinburgh.

20 APPENDIX 2 – TECHNOLOGIES MARKETED OR IN RESEARCH DEVELOPMENT FOR HPV SELF-SAMPLING USE

Technology details Modality Stage of Further develop- information ment Complete kits 1 Rovers Evalyn Brush - Rovers Medical Devices BV (picture: Fig 1, Appendix 4) Kit: all-in-one CE marked http://hpvscreeni ng.co.uk/leaflets/ brush/ for self- evalyn.pdf Rovers Evalyn Brush has been specifically designed for home-based self-sampling and involves no liquid applicator/ sampling handling in the home. It is about 20cm in length and consists of a transparent case with wings. Within the transportatio use casing is a pink stick with a pink plunger at one end and a white brush at the other. At the brush end, a pink n device cap can be clicked onto the case. When the cap is taken off, white brush can be pushed out of the case by pushing the pink plunger towards the transparent casing. Transit: dry (or liquid) Research 28 • Dutch RCT (‘PROHTECT-3B’ trial; n=34,000; NTR3350). Compared two self-sampling devices: (a) the Delphi Screener (see technology 2) and (b) the Rovers Evalyn brush). Recently completed, with paper in preparation (personal communication 5/11/13). 29 l • Dutch study (van Baars et al 2012; n=134). The Rovers Evalyn Brush was used dry with an FTA cartridge (see technology 34). See also research for the Rovers Viba-Brush (technology 11), which is the brush used in the Evalyn device. Ongoing research

• The Rovers Evalyn Brush and the Delphi Screener (see technology 2) are being used for self-sampling in the UK STRATEGIC Study15,16 (Kitchener et al; n=9,600), due to complete in October 2015. 2 Delphi Screener - Delphi-Bioscience BV (picture: Fig 2, Appendix 4) Kit: lavage/ CE marked http://www.delph iscreener.com applicator for self- Previous versions known by the product names Pantarhei Screener and Mermaid. device + sampling separate tube use, but not The Delphi Screener is a single-use sterile device that is pre-filled with a teaspoon amount of water (3 ml yet available

l FTA: Flinders Technology Associates 21

sterile saline). It allows a woman to self-collect a specimen with vaginal and cervical material through a deep Transit: liquid in the UK vaginal lavage. This can be done at home or in the clinic without the need for a speculum examination. The sterile water expels in the vagina around the cervix when the woman pushes the button. The device automatically collects the saline with cervicovaginal cells when the woman releases the button and the device is removed from the vagina. The specimen is transferred, stored and transported in a separate test- tube.

Research 25 • Dutch study (Hesselink et al 2014; n=62 self-sampling with the Delphi Screener). Evaluation of a novel real-time PCR assay, and its utility with self- collected specimens obtained using (a) the Delphi Screener and (b) the Rovers Viba-Brush (see technology 11). 30 • USA study (Jones et el 2013; n=198). 31 • Dutch study (Verhoef et al 2013; n=2,644). 32 • German study (Jentschke et al 2013; n=152). 33 • German study (Jentschke et al 2013; n=100). Compared the analytical and clinical performance of the Abbott RealTime HR HPV Test with the Hybrid Capture 2 assay (HC2) on self-collected cervicovaginal lavage samples. 34 • Italian study (Rossi et al 2011; n=2,400). 35 • German study (Delere et al 2011; n=156). • Dutch study36 called PROHTECT-1 (Gok et al 2010. ISRCTN45527158; n=28,073, n=27,792 self-sampling). 37 • Dutch paper (Gok et al 2012; data pooled from two earlier studies: ISRCTN45527158 PROHTECT-1 used the Delphi Screener (previous Pantarhei Screener/Mermaid), and NTR1851 PROHTECT-2 used the Rovers Viba-Brush; n=26,145). 38 • Finnish study (Virtanen et al 2011; n=2,397). 39 • Finnish study (Virtanen et al 2011; n=1,130 self-sampling). 40 • Italian study (Igidbashian et al 2011; n=205, n=94 self-sampling). 41 • USA study (Jones et al 2012; n=197). 42 • French study (Dalstein et al 2012; in planning: n=50,000). 43 • Dutch study (Hesselink et al 2012, n=355). • Dutch RCT44 recently completed (‘PROHTECT-3B’ trial NTR3350; n=34,000;) compared two self-sampling devices: (a) the Delphi Screener and (b) the Rovers Evalyn Brush (see technology 1). 3 HerSwab - Eve Medical Inc (no UK distributor yet) (picture: Fig 3, Appendix 4) Kit: swab/ CE marked http://www.eve- medical.com/tech applicator for self- nology/ This device has been designed specifically for vaginal self-sampling in the home for the detection of HPV device + sampling DNA. The woman inserts the applicator device and turns the handle. The internal swab automatically separate tube use

22 extends and rotates to collect a sample near the cervix. Transit: dry or

Research liquid No research has been published or completed yet. 4 FLOQSwabs (552C swab) - Copan Flock Technologies SRL, part of Copan Diagnostics Inc. Kit: swab + CE marked http://www.copa nflocktech.com/in UK distributor is Thermo Fisher Scientific (Sterilin) (picture: Fig 4, Appendix 4) separate tube for dex.php/prod/floc professional kedswabs/orderin Transit: dry use only. g/ The sterile flocked swab with a nylon tip comes with a dry plastic transport tube into which it fits to form a http://www.copa unit. FLOQSwabs use short fibre strands which create a thin absorbent layer. It is claimed that cellular nusa.com/media/ material is collected easily and efficiently because FLOQSwabs has a velvet ‘brush-like’ texture which is more In research brochures/Copan _Floqswab_broch effective at dislodging and removing cells. The entire sample is claimed to stay close to the surface of the developmen -web.pdf swab, and is then instantaneously and completely released when mixed with assay reagents or placed in a t for self- sampling http://www.copa buffer solution or transport medium. nflocktech.com/in dex.php/prod/floc Research kedswabs/

• FLOQSwab is being used in a large (n=16,000) prospective Australian RCT called the iPAP trial with the http://www.copa Roche Cobas HPV test, which is PCR-based (personal communication 21/11/13: Professor D Gertig). The nflocktech.com/m self-sampling kit comprises the cotton tipped swab enclosed in a plastic tube within a ziplock bag. The edia/packinserts/ FLOQSwabs_in_tu swab is returned in a pre-paid envelope. The iPAP trial (ID ACTRN12613001104741) is a randomised be_ProductInsert controlled trial of home-based HPV self-sampling for improving participation in cervical screening by never _29.pdf and under screened women, when compared to reminder letters to attend for a Pap test. It will be enrolling between 17/2/2014 and 16/6/2014. 5 Just For Me Kit - Preventive Oncology International (POI) Inc (picture of brush component: Fig 5, Appendix Kit: brush + CE marked http://www.poiin c.org/2012/10/a- 4) separate FTA for blog-for-fall/ card professional use only. http://www.scien A self-collection kit that contains the ‘Just For Me’ self-sampling brush (see technology 12), a solid media cedirect.com/scie transport card (POI-FTA card developed in collaboration with GE Healthcare, see technology 34), an Transit: dry nce/article/pii/S0 envelope, and package with instructions. For sampling the brush is inserted into the vagina, turned 2-3 times In research 09082581300063 2 to the left and 2-3 times to the right. It is then removed and rubbed onto a purple zone on the specimen use for self- processing card and returned with a barcode sticker in the pre-paid envelope. sampling

Research 45 • Peruvian/USA/Chinese study (Levinson et al 2013; n=632; PERCAPS; NCT01338051). The iFTAe micro-card (see technology 34) was used with the Just For Me self-sampling brush. 51,,46,47 Note: POI provided several references in relation to their self-sampling HPV products .

23 Kits with testing service included

6 Qvintip - Aprovix AB (picture: Fig 6, Appendix 4) Kit: swab CE marked http://www.apro vix.com/sv/what- (‘wand’) + for self- is-qvintip/ The Qvintip kit is a blue and white plastic sampling wand (a type of swab), a small plastic sample tube with separate sampling tube, with use. http://www.apro cap, a response envelope and instructions. The self-sampling wand is inserted into the vagina (depth vix.com/sv/how- c.10cm) and rotated once to obtain a small sample of vaginal secretion. It is then removed and allowed to air testing service it-works/ dry for a minute. The wand is then placed inside the sample tube and bent until the white portion snaps off Available in and falls in. The cap is then sealed and the woman disposes of the blue portion of the wand. The sample Transit: dry the UK (in tube is put in the response envelope and posted to the company’s laboratory for analysis. the private healthcare Research sector) 48 • Swedish randomised control study (Broberg et al. 2013; n=8,800; n=800 self-sampling). Compared the effectiveness and cost-effectiveness of routine screening invitation vs routine screening invitation plus phone call vs self-testing. The authors extrapolated from their results to suggest that if the self-test had been offered to non-attendees at the national level, it might have reduced the number of cervical cancers by 17% (73/428). A health economic analysis suggested that the self-test strategy is more effective, and possibly also more cost-effective, than a telephone reminder in terms of cost per eradicated CIN2+, and that the introduction of such a strategy would be cost-saving or at least cost-neutral. 49 • Swedish Phase 0 interventional study (n=8,800; NCT01029990. Completed in 2011. 50 • Swedish study (Wilkstrom et al 2011; n=4,060; n=2,000 self-sampling). 51 • Swedish study (Lindell et al 2011; n=3,618; n=1,426 self-sampling). 52 • Swedish study (Gyllensten et al 2011; n=7,331; n=2,850 self-sampling). 53 • Swedish study (Sanner et al 2009; n=1,107). 54 • Swedish study (Wikstrom et al 2007; n=183). 7 UDoHPVTest (liquid STM version) - UDoTest (Pty) Ltd (picture: Fig 8, Appendix 4) Kit: swab + Available https://www.udot est.com/test/udo- separate tube (direct-to- hpv-test This is a self-collection home HPV screening test. It is sold direct to consumer (woman aged over 29 years), (STM), with consumer as a kit comprised of a swab-based collection device and vial of liquid transport medium, together with a testing service product) South African-based testing service. Transit: liquid Research No published papers for UDoTest were identified. Clinical trials are ongoing in South Africa. 8 UDoHPVTest (dry version) - UDoTest (Pty) Ltd Kit: all-in-one Available https://www.udot est.com/test/udo- brush/ (direct-to- hpv-test

24 A ‘dry’ version of this test (involving no liquid transport medium) is also available, again as a direct-to- applicator/ consumer consumer product that includes a South African-based testing service. transportatio product) n device, with Research testing service No published papers for UDoTest were identified. Transit: dry 9 HPV Home Test (aka HPV-thuitest) - Testing at Home BV (Microbiome Ltd) Kit: all-in-one Available http://www.thuis testenbv.nl/webs brush/ (direct-to- hop/HPV- This kit includes a brush-based sampling device, and is provided with a Netherlands-based testing service applicator/ consumer thuistest/HPV- transportatio product) Thuistest included. The product (kit plus testing service) is available online for purchase by consumers. The product is intended for women who do not want to go to a doctor for cervical screening. Women who test positive n device, with http://www.amaz have an increased risk for cervical cancer and are advised to go to their physician for further patient testing service on.co.uk/s/ref=nb _sb_noss?url=sea management. rch- Transit: dry alias%3Ddrugstor e&field- keywords=hpv+ho me+test&rh=n%3 A65801031%2Ck %3Ahpv+home+te st 10 TAMPAP Test - self sampling kit - Home Test Direct Pty Ltd (HTD) Kit: tampon Status http://www.horiz onscanning.gov.a device, with unclear u/internet/horizo The test involves using an ordinary tampon to collect a sample, then dispatching it in a specially supplied testing service (may have n/publishing.nsf/C been ontent/6B81AEB3 container and pre-paid package to a private laboratory for DNA analysis. However, a current website for this E7EE0001CA2575 company/kit was not found during our searches, so this product may have been discontinued. Transit: not discontinue AD0080F344/%24 known d) File/Aug%20Vol% 2017%20- %20TamPap.pdf Was lunched in http://www.yout ube.com/watch?v the UK as a =GrrmirL21P8 direct-to- consumer http://www.jostr ust.org.uk/node/1 product in 1421 late http://margaretm 2011/early ccartney.com/201 2012 2/10/18/the- overselling-and-

25 lack-of-evidence- for-tampap/

http://www.asa.o rg.uk/Rulings/Adj udications/2012/ 10/Home-Test- Direct-Pty- Ltd/SHP_ADJ_203 992.aspx Collection devices

11 Rovers Viba-Brush - Rovers Medical Devices BV Brush Available for http://www.rover smedicaldevices.c self- om/index.php?pa This device is a brush-head on the end of a stick, and has been specially designed for self-sampling for HPV Transit: dry sampling gina_id=22 testing. It is the more basic version of the Rovers Evalyn Brush (which includes the same brush device within use an applicator, see technology 1). Once the sample has been taken, the device is removed from the vagina, (+ liquid in the brush head is removed from the handle section and placed into the transportation vial. The handle part research) of the device is then discarded.

Research 25 • Dutch study (Hesselink et al 2014; n=112 self-sampling with Viba-Brush). Evaluation of a novel real-time PCR assay, and its utility with self- collected specimens obtained using (a) the Delphi Screener (Delphi- Biosciences) and (b) the Viba-Brush. 55 • Dutch study (‘PROHTECT-2’; Gok et al 2012; n=26,145). The Rovers Viba-Brush was used with a vial containing Universal Collection Medium (see technology 39). 39 • Dutch paper (Gok et al 2012; data pooled from two earlier studies: ISRCTN45527158 (PROHTECT-1: used the Delphi Screener, see technology 2) and NTR1851 (PROHTECT-2: used the Rovers Viba-Brush; n=26,145). 56 • Swedish study (Ostensson et al 2013; modelling of previous data). Used with the iFTAe micro-card (see technology 34). 57 • Dutch study (Dijkstra et al 2012; n=135). Used a Rovers Viba-Brush with a 20ml Thinprep vial/PreservCyc (see technology 35). Results on acceptability: 91% of participants described the brush as easy to use, and many mentioned self-sampling as being less time-consuming as the greatest benefit. Approximately a third were concerned about performing the test properly and said that they would prefer an expert to take the sample. 58 • Dutch/Spanish study (Geraets et al 2013; n=182) with the iFTAe cartridge (see technology 34). 65 • Dutch study (Dijkestra MG et al 2012; n=135). The Rovers Viba-Brush used with a 20ml ThinPrep vial/PreservCyt (see technology 35).

26 59 • Dutch study (Schmeink et al; n=2,065) with a collection tube of SurePath medium (see technology 41). 60 • German study (Mangold 2013; n=103). 67 • Dutch study (Schmeink et al 2013; 2,065). 64 • Swedish study (Ostensson et al 2013). Used with the iFTAe micro-card (see technology 34). 61 • Swedish study (Sanner 2013) with FTA Elute cartridge (see technology 34). 62 • Dutch study (de Bie et al 2011; n=94) with a FTA Elute cartridge (micro card; see technology 34). 63 • USA study (Des Marais et al 2013; n=188). Used a ‘Rovers Brush’ with sample transport medium. Details of sampling device used were not given, but it seems likely to have been the Rovers Viba-Brush. 64 • Dutch study (Lenselink et al 2009; n=96). Viba-Brush was used with the iFTAe cartridge (see technology 34). 12 Just For Me self-sampling brush - Preventive Oncology International (POI) Inc (picture: Fig 6, Appendix Brush CE marked http://www.poiin c.org/2012/10/a- 4) for blog-for-fall/ Transit: dry professional A nylon cervicovaginal brush, specifically designed for self-collection (see also the kit version: technology 5). (FTA card) use only. The brush is inserted, turned two to three times to the left, two to three times to the right, then removed and brushed onto a purple zone on the specimen processing card (see technology 34) and returned in the In research pre-paid envelope. use for self- sampling in Research resource 65 • Peruvian/USA/Chinese study (PERCAPS; Levinson et al 2013; n=632). constrained 51 settings • Chinese/USA study (Belinson et al 2012; n=8,556). 13 Cervical Collection Device - GyneConcepts Inc Sampling In http://gyneconce pts.com ‘tool’/ developmen Described in the product patent as a device, kit and method for self-administration and collection of cervical applicator t http://www.highb device eam.com/doc/1G cell tissue samples, such as for Pap smear testing. Comprises an insertion tube, within which is carried a 1- movable cervical aligning tool with an aligning probe, and a cellular sampling tool with a cellular adhesion 347764004.html surface. The aligning probe and cellular adhesion surface can be selectively movable relative to the insertion Transit: not tube to improve accuracy. known

No research studies/data were identified in our searches.

27 APPENDIX 3 –TECHNOLOGIES THAT MIGHT HAVE POTENTIAL FOR HPV SELF-SAMPLING USE IN THE FUTURE

Note The technologies in this appendix are included for interest, because we identified published research in which they were used for self-sampling (or there was some other reason suggesting that they might have potential for this use). It does not imply that the developer considers them suitable for this indication or that they have any intention of commercialising them for this purpose.

Technology details Modality Stage of Further development information

Complete kits

14 ESwab Collection and Transport System - Copan Flock Technologies SRL, part of Copan Diagnostics Inc. Kit: swab + Available for http://www.copanu sa.com/products/es UK distributor is Thermo Fisher Scientific (Sterilin) separate tube professional wab/ (STM) use http://www.copanu The ESwab (Copan Liquid Amies Elution Swab) Collection and Transport System is a kit comprised of a Nylon sa.com/media/broc Flocked Swab and 1ml of modified Liquid Amies transport medium. The patented flocked swab consists of Transit: liquid hures/Copan_Floqs fine, short filaments fixed at the top of the stick. It is a liquid-based multipurpose (e.g. culture, Gram stains, wab_broch-web.pdf automation) collection and transport system.

Research 66 • Swiss study (Eperon et al 2013; n=120; NCT01316120). A ‘wet’ sample method using ESwab was compared with a ‘dry’ sample method using a Dacron swab with a plastic bag. 67 • French study (Tamalet et al 2012; n=3,767; n=933 self-sampling). This ‘in-house’ device was described as a ‘flocked swab’ from Copan Diagnostics, and the sampled vaginal fluid was placed in a tube of Universal Transport Medium (UTM) (from Abbott). 68 • French study (Tamalet et al 2010; n=123). The same self-sampling device combination was used as in Tamalet et al 2012. 69 • Swiss/Cameroonian study (Navarria et al 2011; n=493). 15 APTIMA Cervical Specimen Collection and Transport kit - Hologic Gen-Probe Inc Kit: brush + Available for http://www.hologic. com/fr/press/media separate tube professional -release/4-4-2013/ Contains an APTIMA cervical specimen collection device (aka APTIMA Cervical Specimen Collection and (STM) use http://www.gen- Transport Brush, see technology 32), a female cleaning swab, and a tube containing 4.3ml of APTIMA cervical probe.com/pdfs/pi/ transport medium (see technology 36). Transit: liquid 502013-EN- RevA.pdf

28 Research 70 http://www.gen- • Kenyan/USA study (Ting et al 2013; n=344). probe.com/pdfs/pos ters/Nugent,%20Eva luation%20of%20th e%20APTIMA%20Ce rvical%20Specimen %20Collection%20a nd%20Transport%2 0Kit.pdf 16 Abbott multi-Collect Specimen Collection Kit - Abbott Molecular Kit: swab + Available http://www.abbott molecular.com/prod separate tube for ucts/infectious- Contains a sterile swab-based collection device (a small swab on a plastic shaft) in packaging and a multi- (STM) professional diseases/realtime- use pcr/multi-collect- collect tube containing 1.2ml of transport buffer with a screw cap. The swab shaft is scored so that it can be specimen-kit.html easily snapped off into the tube after the sample has been taken. The difference between this kit and the Transit: liquid Cervi-Collect Specimen Collection kit (see technology 21) is that it contains a swab rather than a brush for sample collection.

Research A German study is reportedly in progress. 17 digene Female Swab Specimen Collection kit - Qiagen Corp Kit: swab + Available for http://www.qiagen. com/products/catal separate tube professional og/assay- This swab-based kit (product code 5123-1220) contains a Dacron swab and a specimen transport tube (STM) use technologies/compl ete-assay-kits/hpv- containing STM, and is marketed for use with the digene HPV HC2 DNA Test. The swab is inserted into the testing/digene- 0 endocervical canal, and rotated through five 180 turns, alternating in opposite directions, then rubbed firmly Transit: liquid accessories over the transformation zone and withdraw avoiding contact with vaginal mucosa. The swab is then inserted http://palmsuropat into the bottom of the specimen transport tube, the shaft is snapped off at the score line, and the tube h.com/docs/HPVTes recapped. t.pdf

Research 71 • South African study (Adler et al 2013; n=30). 24 • UK RCT (Szarewski et al 2011; n=3,000; 1,500 self-sampling). 18 digene Cervical Sampler (kit) - Qiagen Corp Kit: brush + Available for http://www.qiagen. separate tube com/products/catal professional og/assay- Brush aka Cervical Sample Brush, digene conical-shaped brush, digene brush, Qiagen conical-shaped brush, (STM) use technologies/compl conical cytobrush, Christmas tree sampler. ete-assay-kits/hpv- Transit: liquid testing/digene- This brush-based kit (product code 5122-1220) is comprised of a digene Cervical Sampler brush (see

29 technology 26) and a specimen transport tube of STM, and is marketed for use with the digene HPV HC2 DNA accessories Test. http://palmsuropat h.com/docs/HPVTes Research t.pdf 72 • Mexican study (Lazcano-Ponce et al 2011; n=25,061). The sample brush was placed in a capped collection tube of transport medium. 19 DNAPap Cervical Sampler kit - Qiagen Corp Kit: brush + Available for http://www.qiagen. com/knowledge- separate tube professional and- aka Hybrid Capture 2 (HC2) Cervical Sampler; HC2 Collection Device, Qiagen Cervical Sampler Brush; Conical- (STM) use support/troublesho oting-and- shaped brush; digene conical-shaped brush; digene Cervical Sampler. support/qa-qc- Transit: liquid safety-data/safety- The kit is comprised of the DNAPap Cervical Sampler brush and a digene Specimen Transport Medium (STM) (+ dry in data- sheets?MSDSCountr vial (see technologies 27 and 37). research) yID=UK&ddlKit=DNA Pap+Cervical+Sampl Research er&ddlKitText=DNA 73 Pap+Cervical+Sampl • Chilean study (Leniz et al 2013; n=1,085). er 74 • Chinese/USA study (Guan et al 2013; n=174) with the iFTAe cartridge (see technology 36). 75 • Chinese/USA study (Belinson et al 2012; n=8,556). Women were randomised to self-sample with either a device called the POI/NIH self-sampler (now discontinued) or this device (referred to as ‘the conical-shaped brush from Qiagen’). The self-collected specimens were placed in 20cm3 vials of PreservCyt medium (see technology 35).

Ongoing research Being used in the USA trial76 (n=111; NCT01843478; due to complete March 2014) (identity of device: trialist 20 Hybribio Cervical Sample Collection Kit - Hybribio Ltd Kit: brush + Available for http://hybribio.com /content/sample- separate professional collection-kit/ aka HBCK-F and Female Sample Collection Kit. bottle (STM) use

Contains a collection brush and a bottle containing liquid preservation medium for HPV or STD. The test is Transit: liquid reportedly being used for cervical self-screening in China. No published studies were identified. 21 Cervi-Collect Specimen Collection Kit - Abbott Molecular Kit: brush + Available for http://www.abbott molecular.com/prod separate tube professional ucts/infectious- Contains a Cervi-Collect brush and a Cervi-Collect transport tube containing 2.5ml of Specimen Transport (STM) use diseases/realtimepc r/cervicollect- Buffer. The kit is sold as part of the Abbott RealTime HR HPV assay kit (see also technology 20: multi-Collect specimen- Specimen Collection Kit). An expert consulted thought that the collection brush could be used for self- Transit: liquid collection-kit.html

30 sampling. 22 Kit: swab + Components http://www.news- Cotton wool swab + sterile Nunc CryoTube (ad hoc kit used in research): medical.net/news/201 Swab - Selefa Trade (part of OneMed group) separate tube available for 31218/Simple-HPV- home-tests-could- Tube - Sigma-Aldrich professional identify-women-at- Transit: dry use risk-for-cervical- cancer.aspx?page=2 Research 77 • This swab and tube were combined to make an ad hoc ‘kit’ in a Swedish validation study (Darlin et al 2013; Combined as a http://ac.els- cdn.com/S1386653212 n=121). No transport medium (preservative) was needed. ‘kit’ for 003459/1-s2.0- 78 • research use S1386653212003459- Swedish study (Darlin et al 2013; n=1,500 with 1,000 self-sampling). main.pdf?_tid=038f9d0 8-2b6c-11e3-811d- 00000aacb35d&acdnat =1380723046_fa09044 145159f749f2645f4769 d463b

http://www.ncbi.nlm.n ih.gov/pubmed/23867 008

http://www.sigmaaldri ch.com/catalog/produc t/sigma/v7634?lang=e n®ion=GB&cm _guid=1-_- 100000000000000093 712-_- 36913061585&cm _mmc=Google_Equipm ent-_-search-_- Suppliers%20Brand%2 0Names%20UK_Nunc% 20Branded%20UK-_- CRYOTUBE%20NUNC_ Phrase&cm_guid=1-_- 100000000000000093 712-_- 36913061585&cm_mm c=Google_Equipment- _-search-_- UK%20Suppliers%20Br and%20Names_Nunc% 20Branded%20UK-_- CRYOTUBE%20NUNC_ Phrase

Collection devices

http://www.fisher.co.uk/in 23 Dacron swab - Copan Diagnostics. Thermo Fisher Scientific is the UK distributor Swab Available for dex.php/en/component/s earchenhanced/?searchwo

31 rd= professional %20swab&ordering=&sear Standard Dacron swab, consisting of a long filament enrolled around a stick. Transit: both use chphrase=all liquid and dry https://webshop.fishersci. Research in research com/insight2_uk/getProdu 79 ct.do;jsessionid=A8E53AB9 • UK study (Cadman et al; n=246). Used with specimen transport medium (see technology 39). 18C2AF9DF6E5D4DD7EC7 80 978B.ukhigjavappp9?prod • Canadian pilot study (Zehbe et al; n=49) used a plain polyester Dacron swab and transportation tube (from uctCode=11532483&result SetPosition=0 Copan Diagnostics Sterile Plain Swab; licensed in Canada by Inverness Medical: #552C). 81 • http://louisville.edu/meds French study (Sancho-Garnier et al 2013; n=18,730). Used with a tube of Universal Transport Medium chool/behavioraloncology/ from Abbott Diagnostics. publications/Thomas%20% 82 282006%29%20SBM%20p • USA study (Winer et al 2012; n=518). Dacron-tipped swabs were used with a capped tube containing 1.5 oster%20%28HPV- SS%29.pdf ml of Specimen Transport Medium (see technology 39). http://www.clinicaltrials.g 75 ov/ct2/show/NCT0026626 • Swiss study (Eperon et al 2013; n=120). This ‘dry’ sample method was described as a Dacron swab with a 6?term=hpv+self- test&rank=2 plastic bag, and was compared with a ‘wet’ method described as a ‘flocked’ swab with a tube filled with 1ml http://onlinelibrary.wiley.c of liquid transport medium (see technology 14: ESwab). om/doi/10.1111/1469- 83 • USA/South African study (Adler et al 2013; n=30). Adolescent-aged patients. 0691.12063/pdf

http://www.scitechnol.co m/viable-simple- selfsampling-method-for- human-papillomavirus- detection-among-south- african-adolescents- J7a1.pdf 24 Cytobrush Plus classic version – Carefusion is the UK distributor; CooperSurgical is the manufacturerm Brush Available for http://www.carefus ion.co.uk/medical- professional products/interventi Research Transit: liquid use onal- 84 specialties/obstetric • (in research) USA/Mexican/Peruvian study (Garcia et al 2003; n=334). Cytobrush Plus was used with PreservCyt Solution s- (see technology 35). gynaecology/diagno stic- procedures/cytobru sh-plus-cytobrush- plus.aspx

http://www.cooper surgical.com/ourpr oducts/Pages/Cytob rushPlus.aspx?order 1=C0012&order2=C 0004&order3=C000 5&order4=C0305&o rder5=C0104&order m This product was formerly with MedScand Medical AB 32 6=C0105&order7=C 0112&order8=C012 1&lc=Brushes&nam e=Cytobrush%20Plu s%C2%AE&tc=1 25 Cytobrush Plus GT – Carefusion is the UK distributor; CooperSurgical is the manufacturerw Brush Available for http://www.carefus ion.co.uk/medical- professional products/interventi According to the company this is a newer version of the original ‘Cytobrush Plus’ (see technology 24) which Transit: not use onal- known (but specialties/obstetric has the addition of a ‘Gentle Touch’ tip or protective bulb which is intended to minimise trauma to the s- cervical canal and yield a high quality tissue sample with minimal contamination. The company says that both likely to be gynaecology/diagno the Cytobrush Plus and Cytobrush Plus GT versions have been cited in research papers as being used for self- stic- liquid) procedures/cytobru sampling. sh-plus-cytobrush- plus.aspx

http://www.cooper surgical.com/Docu ments/MD30203_R evA-DFU.pdf 26 digene Cervical Sampler brush - Qiagen Corp Brush Available for http://www.qiagen. professional com/products/catal og/assay- aka Cervical Sampler Brush, digene conical-shaped brush, digene brush, Qiagen conical-shaped brush, conical Transit: liquid use technologies/compl cytobrush, Christmas tree brush. ete-assay-kits/hpv- testing/digene- This brush is sold as part of the digene Cervical Sampler kit (see technology 18) with a specimen transport accessories digene tube of STM, and is marketed for use with the HPV HC2 DNA Test. http://palmsuropat h.com/docs/HPVTes Research t.pdf 85 • Mexican study (Lazcano-Ponce et al 2011; n=25,061). The sample brush was placed in a capped collection tube of transport medium. 86 • Brazilian/Portugese study (Lorenzi et al 2013; n=2,000). The brush was used with a careHPV medium tube (see technology 38). 27 DNAPap Cervical Sampler brush - Qiagen Corp Brush Available for http://www.qiagen. com/knowledge- professional and- Part of the DNAPap Cervical Sampler kit (see technology 19). Transit: liquid use support/troublesho + dry in oting-and- support/qa-qc- research safety-data/safety- data- sheets?MSDSCountr yID=UK&ddlKit=DNA

33 Pap+Cervical+Sampl er&ddlKitText=DNA Pap+Cervical+Sampl er 28 Puritan sterile Polyester Tipped Applicator (swab) - Taylor Scientific Puritan Medical Products Co Swab Available for http://www.puritan medproducts.com/ professional products/detail/593 aka Polyester (Dacron) Swabs, Puritan. The Puritan brand comprises a range of several cotton and polyester Transit: not use 1 known (Dacron) swabs. http://www.taylors cientific.com/taylor Research scientific/Applicator s-Polyester- • The polyester tipped applicator with polystyrene handle (product code ‘25-806 1PD’) is currently being used -Swabs-Puritan- 87 in an ongoing USA study (expected n=5,400 and completion date August 2016). Swab was placed in a P5744.aspx specimen tube. 29 Fisherbrand Cervex-Brush Cervical Cell Sampler - Thermo Fisher Scientific Brush Available for http://www.fishersc i.com/ecomm/servl professional et/fsproductdetail_ The brush has soft, flexible polyethylene bristles, and is designed for professional use for the collection of Transit: liquid use 10652_652881__- 1_0# endocervical, ectocervical and T-zone cells. http://www.science Research direct.com/science/ 88 article/pii/S009082 • USA study (Vanderpool et al 2013; n=31). The sample was placed in the screw-top vial containing Scope 5813012535 mouthwash. http://www.scope mouthwash.com/ 30 Swab-Pak Polyester Dacron Swab - Medical Packaging Corp Swab Available for http://www.medica lpackaging.com/2- professional Large-Polyester- Transit: not use Dacron-Swab-Pack- known Female-Sterile- P84.aspx

http://www.cmaj.ca /content/163/5/513 .full.pdf+html

http://www.ncbi.nl m.nih.gov/pmc/arti cles/PMC2564727/ pdf/337.pdf 31 Cyto-Pak CytoSoft Brush - Medical Packaging Corp Brush Available for http://www.medica lpackaging.com/Cyt professional o-Pak-CytoSoft- Transit: not known

34 use Brush-P94.aspx

32 APTIMA Cervical Specimen Collection and Transport brush - Hologic Gen-Probe Inc Brush Available for http://www.gen- probe.com/pdfs/pi/ professional 502013-EN- This brush is sold as part of the APTIMA Cervical Specimen Collection and Transport kit (see technology 15). In Transit: liquid use RevA.pdf the kit, samples are placed in a tube containing 4.3ml APTIMA cervical transport medium (aka APTIMA Specimen Transport Medium, see technology 36).

Research 79 • Kenyan/USA study (Ting et al 2013; n=344). The sample was placed in APTIMA specimen transport medium. 33 Tampon – company unknown Tampon Unknown http://www.thelanc et.com/journals/lan device onc/article/PIIS147 Research 0-2045(13)70570- 89 9/abstract • Portugese/Brazilian study (Longatto-Filho et al 2012; n=311 self-sampling). Paper reports having used a Transit: not tampon with STM, although no details of this collection device were given. known

Transportation technologies

34 iFTAe micro-card - GE Healthcare (Whatman Inc is a subsidiary) Solid Available for https://promo.gelif esciences.com/na/K transportation professional 13080/products.asp aka Indicating FTA Elute, Whatman FTA Elute card (sometimes referred to as HPV Self Collect). Various device use #.UvN00fl_vPo

formats (card, micro card, cartridge) have been used in self-sampling research. http://uu.diva- Transit: dry portal.org/smash/g The iFTAe matrix is a chemically modified substrate that is incorporated into GE sample collection cards. The et/diva2:611041/FU LLTEXT01 substrate undergoes a colour change when the vaginal sample is placed successfully on the card. The DNA within the sample is lysed and stabilised by the matrix allowing reliable room temperature storage and http://www.gelifesc transportation. iFTAe enables room temperature storage and transportation of dry bio samples. Standard iences.com/webapp /wcs/stores/servlet postal/transportation services can be used. /catalog/en/GELifeS ciences- uk/products/Altern Research ativeProductStructu Published studies (using various versions of the product) include the following. re_18503/

http://uu.diva- Indicating FTA Elute portal.org/smash/g 73 • Peruvian/USA/Chinese study (PERCAPS; Levinson et al 2013; n=632). Samples were collected using the et/diva2:611041/FU ‘Just For Me’ self-sampling brush (see technology 12) and Indicating FTA Elute cards (see technology 34) for LLTEXT01 35 the collection and transportation of specimens. 55 http://www.gelifesc • USA/Mexican/Peruvian study (Levinson et al 2013; n=312; NCT01338051) with a cervical HPV self-sampler iences.com/webapp from POI (possibly technology 12 or the POI/NIH sampler which is now discontinued). /wcs/stores/servlet 70 /catalog/en/GELifeS • Dutch study (de Bie et al 2011; n=94). Used with a Cervex-Brush from Rovers Medical Devices (probably ciences- technology 12: Rovers Viba-Brush). uk/products/Altern Several studies of analytical validity (not using self-collected samples) have been reported90,91. ativeProductStructu re_18503/ Indicating FTA Elute micro card 64 • Swedish study (Ostensson et al 2013; modelling of previous data). Used with the Rovers Viba-Brush (see technology 11). 53 • Peruvian/USA/Chinese study (Levinson et al 2013; n=632; PERCAPS; NCT01338051). The iFTAe micro-card was used with the Just For Me self-sampling brush (see technology 12).

FTA Elute cartridge 69 • Swedish study (Sanner 2013; based data from on earlier studies). Used with the Rovers Viba-Brush (see technology 11). 50 • Chinese/USA study (Guan et al 2013; n=174). Used with the DNAPap Cervical Sampler kit (see technology 19). 66 • Dutch/Spanish study (Geraets et al 2013; n=182). Used with Rovers Viba-Brush (see technology 11). 70 • Dutch study (Bie et al 2013; n=94). Samples collected with ‘Cervex-Brushes’ from Rovers Medical Devices’ (see technologies 1 and 11) and then either rinsed in a Thinprep vial (Cytyc Corp) or applied to the FTA cartridge. 30 • Dutch study (van Baars et al 2012; n=134). The Rovers Evalyn Brush (see technology 1) was used dry with an FTA cartridge. 35 PreservCyt transport medium - Hologic Gen-Probe Inc (was with Cytyc Corp, now a subsidiary of Hologic Transportation Available for http://www.thinpre p.com/hcp/specime Inc) (liquid) professional n_collection/brush_ use spatula.html Research 65 • Dutch study (Dijkstra et al 2012; n=135). Used a Rovers Viba-Brush (see technology 11) with a 20ml Thinprep vial/PreservCyc. 65 • Dutch study (Dijkestra MG et al 2012; n=135). The Rovers Viba-Brush was used with a 20ml ThinPrep vial/PreservCyt. 51 • Chinese/USA study (Belinson et al 2012; n= 8,556). Women were randomised to self-sample with either the ‘conical-shaped brush’ (Qiagen, but unclear whether this refers to the digene Cervical Sampler brush or DNAPap Cervical Sampler, see technologies 29 and 3). The specimens were then placed in 20cm3 vials of

36 PreservCyt medium. 74 • Mexican/USA study (Nieves et al 2013; n=2,049). Used with the POI/NIH self-sampler (now discontinued). 36 APTIMA specimen transport medium - Hologic Gen-Probe Inc Transportation Available for http://www.gen- probe.com/pdfs/pi/ (liquid) professional 502013-EN- Research use RevD.pdf 79 • Kenyan/USA study (Ting et al 2013; n=344). 37 digene Specimen Transport Medium (STM) vial - Qiagen Corp Transportation Available for http://www.qiagen. com/products/catal device professional og/assay- Included in the DNAPap Cervical Sampler kit (see technology 19). use technologies/compl ete-assay-kits/hpv- testing/digene- accessories 38 careHPV medium tube - Qiagen Corp Transportation Available for (liquid) professional Research use 91 • Brasilian/Portugese study (Lorenzi et al 2013; n=2,000). Used with the digene Cervical Sampler brush (see technology 26). 39 Universal Collection Medium - Qiagen Corp Transportation Available for http://www.ncbi.nl m.nih.gov/pubmed/ (liquid) professional 21484793 Research use 63 • Dutch study (‘PROHTECT-2’; Gok et al 2012; n=26,145). Used with the Rovers Viba-Brush (see technology 11). 40 Copan transport medium – Copan Diagnostics Inc Transportation Available for http://www.copanu sa.com/search/sres (liquid) professional ults/ Research use 92 • French study (Piana et al 2011; n=9,334; n=4,400 self-sampling). Used Copan transport medium with an unspecified vaginal swab. 41 SurePath Preservative Fluid vial - Becton Dickinson UK Ltd Transportation Available for http://www.bd.com /tripath/physicians/ (liquid) professional pi_index.asp Research use 67 http://www.bd.com • Dutch study (Schmeink et al; n=2,065). Used with the Rovers Viba-Brush (see technology 11). /tripath/products/o utside_us/outside_ us_sp.asp

http://onlinelibrary. wiley.com/doi/10.1 002/ijc.27986/pdf

37 APPENDIX 4 – PICTURES OF SOME OF THE TECHNOLOGIES TheThe

Figure 1. Rovers Evalyn Brush (technology 1, Appendix 2). Copyright Rovers Medical Devices BV

Figure 2. Delphi Screener (technology 2, Appendix 2). Copyright Delphi Bioscience BV

Figure 3. HerSwab (technology 3, Appendix 2). Copyright Eve Medical Inc

Figure 4. FLOQSwabs (technology 4 [image on the right], Appendix 2). Copyright Copan Flock Technologies srl

Figure 5. Just For Me (technologies 5 [kit] and 12 [brush component], Appendix 2). Copyright Preventive Oncology International Inc

Figure 6. Qvintip (technology 6, Appendix 2). Copyright Aprovix AB

Figure 7. UDoHPVTest (technology 7, Appendix 2). Copyright UDoTest

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The NIHR Horizon Scanning Centre, University of Birmingham, United Kingdom [email protected] http://www.hsc.nihr.ac.uk